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Mechanisms of resistance to the BCR-ABL1 allosteric inhibitor asciminib

Leukemia volume 31, pages 2844–2847 (2017)Cite this article

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The development of asciminib (ABL001),1 a highly potent and specific ABL1/ABL2/BCR-ABL1 tyrosine kinase inhibitor (TKI) with an allosteric mechanism of action that culminated from research in academic and pharmaceutical industry laboratories spanning more than a decade. Currently in clinical trials for relapsed/refractory Philadelphia chromosome-positive (Ph+) leukemia patients (ClinicalTrials.gov: NCT02081378), asciminib represents a major advance from the structurally related, prototype compounds GNF-2 and GNF-5.2,3,4 We investigated mechanisms of asciminib resistance and identified two major categories: (1) upregulation of the ABCG2 efflux pump, resulting in undetectable intracellular asciminib levels and (2) emergence of BCR-ABL1 mutations at the myristoyl-binding site and at a distant residue.

KCL-22asciminib-R cells exhibited two mutations at similar allelic frequencies:9 BCR-ABL1M244V near the ATP-binding site and BCR-ABL1A337V in the myristoyl-binding pocket (Supplementary Table S2), and single-cell sorting followed by clonal sequencing revealed a BCR-ABL1M244V/A337V compound mutation.10, 11 KCL-22asciminib-R cells were completely insensitive to asciminib (IC50: 10 000 nM as compared to 2.2 nM for parental KCL-22 cells), but remained sensitive to ATP-binding site TKIs (Figure 2c; Supplementary Figure S5a; Supplementary Table S1). LC/MS-MS showed comparable intracellular asciminib levels in KCL-22asciminib-R and KCL-22 cells, and there was no evidence of either altered effectiveness of asciminib against KCL-22asciminib-R cells by inclusion of an efflux pump inhibitor or upregulation of an efflux pump by qPCR or ABCG2 immunoblot (Supplementary Figure S5b–e). Sequencing of increasingly asciminib-resistant cells collected in the process of generating the final KCL-22asciminib-R cell line revealed a progression from BCR-ABL1A337V to BCR-ABL1M244V/A337V (Figure 2d). The reported asciminib IC50 value of 702 nM for KCL-22A337V cells1 is consistent with the inability of this mutation alone to confer the high-level resistance observed in KCL-22asciminib-R cells. The BCR-ABL1M244V/A337V compound mutant confers high-level asciminib resistance but inclusion of clinically achievable concentrations of imatinib lead to outgrowth of BCR-ABL1S229P/T315I at the expense of BCR-ABL1M244V/A337V (Supplementary Figure S6), highlighting a potential complication of addressing asciminib resistance by switching to or including an ATP-binding site TKI.

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Acknowledgements

WQ is supported by NSFC (81400105) and Science and Technology Planning Project of Guangdong (2014A020212185). This work was supported by NIH/NCI R01CA178397 (MD, TO) and Cancer Center Support Grant P30CA042014.

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Author notes

  1. W Qiang and O Antelope: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Nanfang Hospital, Southern Medical University, GuangZhou, China

    W Qiang

  2. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    W Qiang, O Antelope, M S Zabriskie, A D Pomicter, N A Vellore, M W Deininger & T O’Hare

  3. ARUP Laboratories, Salt Lake City, UT, USA

    P Szankasi & T W Kelley

  4. Service d’Hématologie Adulte and INSERM UMR1160, Hospital Saint-Louis, Paris, France

    D Rea

  5. Laboratory of Hematology, University Hospital Saint- Louis and EA3518, University Paris Diderot, Paris

    J M Cayuela

  6. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    T W Kelley

  7. Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA

    M W Deininger & T O’Hare

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Correspondence to T O’Hare.

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Competing interests

TWK has financial interests to declare: Novartis speaker's bureau, Novartis advisory board. DR receives honoraria from BMS, Novartis, Incyte and Pfizer for non-promotional scientific lectures or advisory boards and is an investigator of Novartis-sponsored CABL001X2101 phase I trial. The remaining authors declare no conflict of interest.

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Qiang, W., Antelope, O., Zabriskie, M. et al. Mechanisms of resistance to the BCR-ABL1 allosteric inhibitor asciminib. Leukemia 31, 2844–2847 (2017). https://doi.org/10.1038/leu.2017.264

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